Publications
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Kitonsa J, Kamacooko O, Ruzagira E, et al., 2023, A phase I COVID-19 vaccine trial among SARS-CoV-2 seronegative and seropositive individuals in Uganda utilizing a self-amplifying RNA vaccine platform: screening and enrollment experiences, Human Vaccines and Immunotherapeutics, Vol: 19, Pages: 1-8, ISSN: 1554-8600
We report the screening and enrollment process for a phase I vaccine trial in Masaka, Uganda that investigated the safety and immunogenicity of a self-amplifying SARS-CoV-2 RNA vaccine amongst individuals with and without antibodies to SARS-CoV-2. Participant screening and enrollment were conducted between December 2021 and April 2022. Individuals were eligible if they were aged between 18 and 45 years, healthy, and never vaccinated against COVID-19. SARS-CoV-2 antibody status was determined using two point-of-care rapid tests, i.e. Multi G (MGFT3) and Standard Q (Standard Q COVID-19 IgM/IgG Plus). Data were entered and managed in OpenClinica. Analyses were performed and presented descriptively. A total of 212 individuals were screened and 43(20.3%) enrolled. The most common reasons for exclusion were ≥ grade 1 laboratory abnormalities (39, 18.4%), followed by discordant SARS-CoV-2 antibody results (23, 10.9%). While the first 38 participants were quickly enrolled over a period of 9 weeks, it took another 9 weeks to enroll the remaining five, as antibody negative participants became scarce during the surge of the Omicron variant. The SARS-CoV-2 antibody positivity rate was determined to be 60.8% and 84.4% in each half of the 18 months of screening respectively. The mean age (±Standard Deviation, SD) of screened and enrolled participants was 27.7 (±8.1) and 30.2 (±8.3) years respectively. We demonstrated that it is feasible to successfully screen and enroll participants for COVID-19 vaccine trials in Uganda in the time of a pandemic. Our experiences may be useful for investigators planning to undertake similar work in Africa.
Horvath A, Rogers L, Pollakis G, et al., 2023, Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?, Frontiers in Immunology, Vol: 13, Pages: 1-16, ISSN: 1664-3224
Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.
Gombe B, Streatfield C, Leal L, et al., 2022, Optimization and validation of an ELISA assay for the determination of antibody responses to CN54gp140 and AIDSVAX BE for use in the Phase IIb PrEPVacc vaccine trial, PLoS One, Vol: 17, ISSN: 1932-6203
PrEPVacc is an international, multi-centre, double-blind vaccine study comparing experimental combination vaccine regimens including DNA/AIDSVAX BE and DNA/CN54gp140 with placebo control. Simultaneously, daily oral PrEP is compared for efficacy against daily Truvada in the context of the current PrEP availability situation at the study sites. An important clinical trial outcome is the accurate measurement of in vivo antibody titer induced through vaccination. Here we report the validation of two ELISAs for CN54gp140 and AIDSVAX BE at Uganda Virus Research Institute that demonstrates precision, specificity, and robustness for assessing the reciprocal antibody end point titer in human serum. This is a critical endpoint for determining whether vaccination can provide any protection against HIV in populations at risk of acquiring HIV.
Dalel J, Ung SK, Hayes P, et al., 2021, HIV-1 infection and the lack of viral control are associated with greater expression of interleukin-21 receptor on CD8(+) T cells, AIDS, Vol: 35, Pages: 1167-1177, ISSN: 0269-9370
Objectives: Interleukin-21 (IL-21) has been linked with the generation of virus-specific memory CD8+ T cells following acute infection with HIV-1 and reduced exhaustion of CD8+ T cells. IL-21 has also been implicated in the promotion of CD8+ T-cell effector functions during viral infection. Little is known about the expression of interleukin-21 receptor (IL-21R) during HIV-1 infection or its role in HIV-1-specific CD8+ T-cell maintenance and subsequent viral control.Methods: We compared levels of IL-21R expression on total and memory subsets of CD8+ T cells from HIV-1-negative and HIV-1-positive donors. We also measured IL-21R on antigen-specific CD8+ T cells in volunteers who were positive for HIV-1 and had cytomegalovirus-responding T cells. Finally, we quantified plasma IL-21 in treatment-naive HIV-1-positive individuals and compared this with IL-21R expression.Results: IL-21R expression was significantly higher on CD8+ T cells (P = 0.0256), and on central memory (P = 0.0055) and effector memory (P = 0.0487) CD8+ T-cell subsets from HIV-1-positive individuals relative to HIV-1-negative individuals. For those infected with HIV-1, the levels of IL-21R expression on HIV-1-specific CD8+ T cells correlated significantly with visit viral load (r = 0.6667, P = 0.0152, n = 13) and inversely correlated with plasma IL-21 (r = −0.6273, P = 0.0440, n = 11). Lastly, CD8+ T cells from individuals with lower set point viral load who demonstrated better viral control had the lowest levels of IL-21R expression and highest levels of plasma IL-21.Conclusion: Our data demonstrates significant associations between IL-21R expression on peripheral CD8+ T cells and viral load, as well as disease trajectory. This suggests that the IL-21 receptor could be a novel marker of CD8+ T-cell dysfunction during HIV-1 infection.
Makinde J, Nduati EW, Freni-Sterrantino A, et al., 2021, A novel sample selection approach to aid the identification of factors that correlate wth the control of HIV-1 infection, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224
Individuals infected with HIV display varying rates of viral control and disease progression, with a small percentage of individuals being able to spontaneously control infection in the absence of treatment. In attempting to define the correlates associated with natural protection against HIV, extreme heterogeneity in the datasets generated from systems methodologies can be further complicated by the inherent variability encountered at the population, individual, cellular and molecular levels. Furthermore, such studies have been limited by the paucity of well-characterised samples and linked epidemiological data, including duration of infection and clinical outcomes. To address this, we selected 10 volunteers who rapidly and persistently controlled HIV, and 10 volunteers each, from two control groups who failed to control (based on set point viral loads) from an acute and early HIV prospective cohort from East and Southern Africa. A propensity score matching approach was applied to control for the influence of five factors (age, risk group, virus subtype, gender, and country) known to influence disease progression on causal observations. Fifty-two plasma proteins were assessed at two timepoints in the 1st year of infection. We independently confirmed factors known to influence disease progression such as the B*57 HLA Class I allele, and infecting virus Subtype. We demonstrated associations between circulating levels of MIP-1α and IL-17C, and the ability to control infection. IL-17C has not been described previously within the context of HIV control, making it an interesting target for future studies to understand HIV infection and transmission. An in-depth systems analysis is now underway to fully characterise host, viral and immunological factors contributing to control.
Joachim A, Msafiri F, Onkar S, et al., 2020, Frequent and Durable Anti-HIV Envelope VIV2 IgG Responses Induced by HIV-1 DNA Priming and HIV-MVA Boosting in Healthy Tanzanian Volunteers, Vaccines, Vol: 8, Pages: 681-681
<jats:p>We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty vaccinees received a third HIV-MVA boost after three years in the HIVIS06 trial. IgG and IgG antibody subclasses to gp70V1V2 proteins of HIV-1 A244, CN54, Consensus C, and Case A2 were analysed using an enzyme-linked immunosorbent assay (ELISA). Cyclic V2 peptides of A244, Consensus C, and MN were used in a surface plasmon resonance (SPR) assay. Four weeks after the second HIV-MVA, anti-V1V2 IgG antibodies to A244 were detected in 97% of HIVIS03 vaccinees, in 75% three years later, and in 95% after the third HIV-MVA. Anti-CN54 V1V2 IgG was detectable in 48% four weeks after the second HIV-MVA. The SPR data supported the findings. The IgG response was predominantly IgG1. Four weeks after the second HIV-MVA, 85% of vaccinees had IgG1 antibodies to V1V2 A244, which persisted in 25% for three-years. IgG3 and IgG4 antibodies to V1V2 A244 were rare. In conclusion, the HIV-DNA/MVA vaccine regimen induced durable V1V2 IgG antibody responses in a high proportion of vaccinees.</jats:p>
Msafiri F, Joachim A, Held K, et al., 2020, Frequent anti-V1V2 responses induced by HIV-DNA followed by HIV-MVA with or without CN54rgp140/GLA-AF in healthy African volunteers, Microorganisms, Vol: 8, Pages: 1-19, ISSN: 2076-2607
Antibody responses that correlated with reduced risk of HIV acquisition in the RV144 efficacy trial were assessed in healthy African volunteers who had been primed three times with HIV-DNA (subtype A, B, C) and then randomized into two groups; group 1 was boosted twice with HIV-MVA (CRF01_AE) and group 2 with the same HIV-MVA coadministered with subtype C envelope (Env) protein (CN54rgp140/GLA-AF). The fine specificity of plasma Env-specific antibody responses was mapped after the final vaccination using linear peptide microarray technology. Binding IgG antibodies to the V1V2 loop in CRF01_AE and subtype C Env and Env-specific IgA antibodies were determined using enzyme-linked immunosorbent assay. Functional antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody responses were measured using luciferase assay. Mapping of linear epitopes within HIV-1 Env demonstrated strong targeting of the V1V2, V3, and the immunodominant region in gp41 in both groups, with additional recognition of two epitopes located in the C2 and C4 regions in group 2. A high frequency of V1V2-specific binding IgG antibody responses was detected to CRF01_AE (77%) and subtype C antigens (65%). In conclusion, coadministration of CN54rgp140/GLA-AF with HIV-MVA did not increase the frequency, breadth, or magnitude of anti-V1V2 responses or ADCC-mediating antibodies induced by boosting with HIV-MVA alone.
Clark A, Jit M, Warren-Gash C, et al., 2020, Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study, LANCET GLOBAL HEALTH, Vol: 8, Pages: 1003-1017, ISSN: 2214-109X
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Joachim A, Ahmed MIM, Pollakis G, et al., 2020, Induction of Identical IgG HIV-1 Envelope Epitope Recognition Patterns After Initial HIVIS-DNA/MVA-CMDR Immunization and a Late MVA-CMDR Boost, Frontiers in Immunology, Vol: 11
Nadai Y, Held K, Joseph S, et al., 2019, Envelope-specific recognition patterns of HIV vaccine-induced IgG antibodies are linked to immunogen structure and sequence, Frontiers in Immunology, Vol: 10, Pages: 1-14, ISSN: 1664-3224
Background: A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines.Methods: Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, n = 11 from UK) and TaMoVac01 (TMV01, n = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 μg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition.Results: After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG (p < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group.Conclusions: IgG recognition of linear antigenic Env regions differe
Joseph S, Kaleebu P, Ruzagira E, et al., 2019, OC 8491 PREPVACC: A PHASE III, MAMS ADAPTIVE PROPHYLACTIC HIV VACCINE TRIAL WITH A SECOND RANDOMISATION TO COMPARE F/TAF WITH TDF/FTC PREP, BMJ Global Health, Vol: 4, Pages: A10.1-A10
<jats:sec><jats:title>Background</jats:title><jats:p>There remains an urgent need for a prophylactic HIV vaccine to control generalised epidemics. PrEP has demonstrated effectiveness of 86% and is recommended by WHO; uptake is generally high, but retention is disappointing in some settings. The EDCTP2 project PrEPVacc will assess the efficacy of two combination prophylactic vaccine regimens (DNA, MVA and Env protein/adjuvant) each compared to placebo and the proportion of infections averted by F/TAF in comparison to TDF/FTC. A Registration Cohort, recruiting HIV negative volunteers at risk of HIV will precede the trial.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The PrEPVacc partnership agreed that 70% vaccine efficacy had public health relevance. The trial uses <jats:italic>nstage</jats:italic> software for multi-arm, multi-stage designs (MAMS) and the averted infections ratio (AIR) methodology with participants randomised (i) 1:1:1 to active product or placebo (ii) 1:1 to TDF/FTC : F/TAF until week 26 (presumed peak immunogenicity). Access to PrEP in the Registration Cohort and after week 26 will be standard of care. HIV seroconversions occurring between weeks 0–26 will inform the PrEP analysis, incorporating HIV incidence amongst those who do not take up PrEP locally in the Registration Cohort. Seroconversions after week 26 will inform vaccine analyses.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Up to 556 participants per group affords 92% power to detect vaccine efficacy of 70% at the final analysis, assuming incidence of 4/100-person years and 10% loss with 81% and 97% power to conclude that F/TAF can avert half or more of the infections prevented by TDF/FTC if effectiveness of TDF/FTC is 70% and 80%, respectively.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats
Viegas EO, Kroidl A, Munseri PJ, et al., 2018, Optimizing the immunogenicity of HIV prime-boost DNA-MVA-rgp140/GLA vaccines in a phase II randomized factorial trial design, PLoS One, Vol: 13, Pages: 1-19, ISSN: 1932-6203
BackgroundWe evaluated the safety and immunogenicity of (i) an intradermal HIV-DNA regimen given with/without intradermal electroporation (EP) as prime and (ii) the impact of boosting with modified vaccinia virus Ankara (HIV-MVA) administered with or without subtype C CN54rgp140 envelope protein adjuvanted with Glucopyranosyl Lipid A (GLA-AF) in volunteers from Tanzania and Mozambique.MethodsHealthy HIV-uninfected adults (N = 191) were randomized twice; first to one of three HIV-DNA intradermal priming regimens by needle-free ZetaJet device at weeks 0, 4 and 12 (Group I: 2x0.1mL [3mg/mL], Group II: 2x0.1mL [3mg/mL] plus EP, Group III: 1x0.1mL [6mg/mL] plus EP). Second the same volunteers received 108 pfu HIV-MVA twice, alone or combined with CN54rgp140/GLA-AF, intramuscularly by syringe, 16 weeks apart. Additionally, 20 volunteers received saline placebo.ResultsVaccinations and electroporation did not raise safety concerns. After the last vaccination, the overall IFN-γ ELISpot response rate to either Gag or Env was 97%. Intradermal electroporation significantly increased ELISpot response rates to HIV-DNA-specific Gag (66% group I vs. 86% group II, p = 0.026), but not to the HIV-MVA vaccine-specific Gag or Env peptide pools nor the magnitude of responses. Co-administration of rgp140/GLA-AF with HIV-MVA did not impact the frequency of binding antibody responses against subtype B gp160, C gp140 or E gp120 antigens (95%, 99%, 79%, respectively), but significantly enhanced the magnitude against subtype B gp160 (2700 versus 300, p<0.001) and subtype C gp140 (24300 versus 2700, p<0.001) Env protein. At relatively low titers, neutralizing antibody responses using the TZM-bl assay were more frequent in vaccinees given adjuvanted protein boost.ConclusionIntradermal electroporation increased DNA-induced Gag response rates but did not show an impact on Env-specific responses nor on the magnitude of responses. Co-administration of HIV-MVA with rgp140/GLA-AF significa
Haidari G, Cope A, Miller A, et al., 2017, Combined skin and muscle vaccination differentially impact the quality of effector T cell functions: the CUTHIVAC-001 randomized trial, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers.
Jespers V, Kyongo J, Joseph S, et al., 2017, A longitudinal analysis of the vaginal microbiota and vaginal immune mediators in women from sub-Saharan Africa, Scientific Reports, Vol: 7
<jats:title>Abstract</jats:title><jats:p>In cross-sectional studies increased vaginal bacterial diversity has been associated with vaginal inflammation which can be detrimental for health. We describe longitudinal changes at 5 visits over 8 weeks in vaginal microbiota and immune mediators in African women. Women (N = 40) with a normal Nugent score at all visits had a stable lactobacilli dominated microbiota with prevailing <jats:italic>Lactobacillus iners</jats:italic>. Presence of prostate-specific antigen (proxy for recent sex) and being amenorrhoeic (due to progestin-injectable use), but not recent vaginal cleansing, were significantly associated with microbiota diversity and inflammation (controlled for menstrual cycle and other confounders). Women (N = 40) with incident bacterial vaginosis (Nugent 7–10) had significantly lower concentrations of lactobacilli and higher concentrations of <jats:italic>Gardnerella vaginalis</jats:italic>, <jats:italic>Atopobium vaginae</jats:italic>, and <jats:italic>Prevotella bivia</jats:italic>, at the incident visit and when concentrations of proinflammatory cytokines (IL-1β, IL-12p70) were increased and IP-10 and elafin were decreased. A higher ‘composite-qPCR vaginal-health-score’ was directly associated with decreased concentrations of proinflammatory cytokines (IL-1α, IL-8, IL-12(p70)) and increased IP-10. This longitudinal study confirms the inflammatory nature of vaginal dysbiosis and its association with recent vaginal sex and progestin-injectable use. A potential role for proinflammatory mediators and IP-10 in combination with the vaginal-health-score as predictive biomarkers for vaginal dysbiosis merits further investigation.</jats:p>
Bauer A, Podola L, Mann P, et al., 2017, Preferential Targeting of Conserved Gag Regions after Vaccination with a Heterologous DNA Prime-Modified Vaccinia Virus Ankara Boost HIV-1 Vaccine Regimen, Journal of Virology, Vol: 91, ISSN: 0022-538X
<jats:title>ABSTRACT</jats:title> <jats:p> Prime-boost vaccination strategies against HIV-1 often include multiple variants for a given immunogen for better coverage of the extensive viral diversity. To study the immunologic effects of this approach, we characterized breadth, phenotype, function, and specificity of Gag-specific T cells induced by a DNA-prime modified vaccinia virus Ankara (MVA)-boost vaccination strategy, which uses mismatched Gag immunogens in the TamoVac 01 phase IIa trial. Healthy Tanzanian volunteers received three injections of the DNA-SMI vaccine encoding a subtype B and AB-recombinant Gag <jats:sub>p37</jats:sub> and two vaccinations with MVA-CMDR encoding subtype A Gag <jats:sub>p55</jats:sub> . Gag-specific T-cell responses were studied in 42 vaccinees using fresh peripheral blood mononuclear cells. After the first MVA-CMDR boost, vaccine-induced gamma interferon-positive (IFN-γ <jats:sup>+</jats:sup> ) Gag-specific T-cell responses were dominated by CD4 <jats:sup>+</jats:sup> T cells ( <jats:italic>P</jats:italic> < 0.001 compared to CD8 <jats:sup>+</jats:sup> T cells) that coexpressed interleukin-2 (IL-2) (66.4%) and/or tumor necrosis factor alpha (TNF-α) (63.7%). A median of 3 antigenic regions were targeted with a higher-magnitude median response to Gag <jats:sub>p24</jats:sub> regions, more conserved between prime and boost, compared to those of regions within Gag <jats:sub>p15</jats:sub> (not primed) and Gag <jats:sub>p17</jats:sub> (less conserved; <jats:italic>P</jats:italic> < 0.0001 for both). Four regions within Gag <ja
Ford D, Muzambi M, Nkhata MJ, et al., 2017, Implementation of antiretroviral therapy for life in pregnant/Breastfeeding HIV+ women (Option B+) alongside rollout and changing guidelines for art initiation in rural Zimbabwe: the Lablite project experience, JAIDS: Journal of Acquired Immune Deficiency Syndromes, Vol: 74, Pages: 508-516, ISSN: 1525-4135
Background: Lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (Option B+) was rolled out in Zimbabwe from 2014, with simultaneous raising of the CD4 treatment threshold to 500 cells per cubic millimeter in nonpregnant/breastfeeding adults and children 5 years and over.Methods: Lablite is an implementation project in Zimbabwe, Malawi, and Uganda evaluating ART rollout. Routine patient-level data were collected for 6 months before and 12 months after Option B+ rollout at a district hospital and 3 primary care facilities in Zimbabwe (2 with outreach ART and 1 with no ART provision before Option B+).Results: Between September 2013 and February 2015, there were 1686 ART initiations in the 4 facilities: 91% adults and 9% children younger than 15 years. In the 3 facilities with established ART, initiations rose from 300 during 6 months before Option B+ to 869 (2.9-fold) and 463 (1.5-fold), respectively, 0–6 months and 6–12 months after Option B+. Post-Option B+, an estimated 43% of pregnant/breastfeeding women needed ART for their own health, based on World Health Organization stage 3/4 or CD4 ≤350 per cubic millimeter (64% for CD4 ≤500). Seventy-four men (22%) and 123 nonpregnant/breastfeeding women (34%) initiated ART with CD4 >350 after the CD4 threshold increase. Estimated 12-month retention on ART was 79% (69%–87%) in Option B+ women (significantly lower in younger women, P = 0.01) versus 93% (91%–95%) in other adults (difference P < 0.001).Conclusions: There were increased ART initiations in all patient groups after implementation of World Health Organization 2013 guidelines. Retention of Option B+ women was poorer than retention of other adults; younger women require attention because they are more likely to disengage from care.
Joseph S, Quinn K, Greenwood A, et al., 2017, A comparative phase I study of combination, homologous subtype-C DNA, MVA, and Env gp140 protein/adjuvant HIV vaccines in two immunization regimes, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The ap
Nkhata MJ, Muzambi M, Ford D, et al., 2016, Shifting human resources for health in the context of ART provision: qualitative and quantitative findings from the Lablite baseline study, BMC Health Services Research, Vol: 16, Pages: 1-10, ISSN: 1472-6963
BackgroundLablite is an implementation project supporting and studying decentralized antiretroviral therapy (ART) rollout to rural communities in Malawi, Uganda and Zimbabwe. Task shifting is one of the strategies to deal with shortage of health care workers (HCWs) in ART provision. Evaluating Human Resources for Health (HRH) optimization is essential for ensuring access to ART. The Lablite project started with a baseline survey whose aim was to describe and compare national and intercountry delivery of ART services including training, use of laboratories and clinical care.MethodsA cross-sectional survey was conducted between October 2011 and August 2012 in a sample of 81 health facilities representing different regions, facility levels and experience of ART provision in Malawi, Uganda and Zimbabwe. Using a questionnaire, data were collected on facility characteristics, human resources and service provision. Thirty three (33) focus group discussions were conducted with HCWs in a subset of facilities in Malawi and Zimbabwe.ResultsThe survey results showed that in Malawi and Uganda, primary care facilities were run by non-physician clinical officers/medical assistants while in Zimbabwe, they were run by nurses/midwives. Across the three countries, turnover of staff was high especially among nurses. Between 10 and 20% of the facilities had at least one clinical officer/medical assistant leave in the 3 months prior to the study. Qualitative results show that HCWs in ART and non-ART facilities perceived a shortage of staff for all services, even prior to the introduction of ART provision. HCWs perceived the introduction of ART as having increased workload. In Malawi, the number of people on ART and hence the workload for HCWs has further increased following the introduction of Option B+ (ART initiation and life-long treatment for HIV positive pregnant and lactating women), resulting in extended working times and concerns that the quality of services have been affected. F
Joseph S, Quinn K, Greenwood A, et al., 2016, UK HVC 003: A Phase I Clinical Trial Exploring a Strategy to Maximise HIV Antibody Responses using Subtype C DNA, MVA and GLA Adjuvanted gp140, Conference on HIV Research for Prevention (HIV R4P), Publisher: MARY ANN LIEBERT, INC, Pages: 99-99, ISSN: 0889-2229
Joachim A, Bauer A, Joseph S, et al., 2016, Boosting with Subtype C CN54rgp140 Protein Adjuvanted with Glucopyranosyl Lipid Adjuvant after Priming with HIV-DNA and HIV-MVA Is Safe and Enhances Immune Responses: A Phase I Trial., PLOS One, Vol: 11, ISSN: 1932-6203
BACKGROUND: A vaccine against HIV is widely considered the most effective and sustainable way of reducing new infections. We evaluated the safety and impact of boosting with subtype C CN54rgp140 envelope protein adjuvanted in glucopyranosyl lipid adjuvant (GLA-AF) in Tanzanian volunteers previously given three immunizations with HIV-DNA followed by two immunizations with recombinant modified vaccinia virus Ankara (HIV-MVA). METHODS: Forty volunteers (35 vaccinees and five placebo recipients) were given two CN54rgp140/GLA-AF immunizations 30-71 weeks after the last HIV-MVA vaccination. These immunizations were delivered intramuscularly four weeks apart. RESULTS: The vaccine was safe and well tolerated except for one episode of asymptomatic hypoglycaemia that was classified as severe adverse event. Two weeks after the second HIV-MVA vaccination 34 (97%) of the 35 previously vaccinated developed Env-specific binding antibodies, and 79% and 84% displayed IFN-γ ELISpot responses to Gag and Env, respectively. Binding antibodies to subtype C Env (included in HIV-DNA and protein boost), subtype B Env (included only in HIV-DNA) and CRF01_AE Env (included only in HIV-MVA) were significantly boosted by the CN54rgp140/GLA-AF immunizations. Functional antibodies detected using an infectious molecular clone virus/peripheral blood mononuclear cell neutralization assay, a pseudovirus/TZM-bl neutralization assay or by assays for antibody-dependent cellular cytotoxicity (ADCC) were not significantly boosted. In contrast, T-cell proliferative responses to subtype B MN antigen and IFN-γ ELISpot responses to Env peptides were significantly enhanced. Four volunteers not primed with HIV-DNA and HIV-MVA before the CN54rgp140/GLA-AF immunizations mounted an antibody response, while cell-mediated responses were rare. After the two Env subtype C protein immunizations, a trend towards higher median subtype C Env binding antibody titers was found in vaccinees who had received HIV-DN
Cosgrove CA, Lacey CJ, Cope AV, et al., 2016, Comparative immunogenicity of HIV-1 gp140 vaccine delivered by parenteral, and mucosal routes in female volunteers; MUCOVAC2, a randomized two centre study, PLOS One, Vol: 11, ISSN: 1932-6203
BackgroundDefining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.MethodsIn this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.ResultsThree IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.ConclusionsThese data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.
Gautam R, Borgdorff H, Jespers V, et al., 2015, Correlates of the molecular vaginal microbiota composition of African women, BMC Infectious Diseases, Vol: 15
Kyongo JK, Crucitti T, Menten J, et al., 2015, P06.05 Dynamics of vaginal immune correlates and microbiota in women from sub-saharan africa, Sexually Transmitted Infections, Vol: 91, Pages: A116.1-A116, ISSN: 1368-4973
Kyongo JK, Crucitti T, Menten J, et al., 2015, Cross-Sectional Analysis of Selected Genital Tract Immunological Markers and Molecular Vaginal Microbiota in Sub-Saharan African Women, with Relevance to HIV Risk and Prevention, Clinical and Vaccine Immunology, Vol: 22, Pages: 526-538, ISSN: 1556-6811
<jats:title>ABSTRACT</jats:title><jats:p>Data on immune mediators in the genital tract and the factors that modulate them in sub-Saharan women are limited. Cervicovaginal lavage (CVL) samples from 430 sexually active women from Kenya, South Africa, and Rwanda were analyzed for 12 soluble immune mediators using Bio-Plex and Meso Scale Discovery multiplex platforms, as well as single enzyme-linked immunosorbent assays. Ten bacterial species were quantified in vaginal swab samples. Bacterial vaginosis (BV) was defined by Nugent scoring. CVL samples from HIV-infected women showed a clear-cut proinflammatory profile. Pregnant women, adolescents, and women engaging in traditional vaginal practices differed in specific soluble markers compared to reference groups of adult HIV-negative women. Cervical mucus, cervical ectopy, abnormal vaginal discharge, and having multiple sex partners were each associated with an increase in inflammatory mediators. The levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-12(p70), and IL-8 were elevated, whereas the IL-1RA/IL-1(α+β) ratio decreased in women with BV. The level of gamma interferon-induced protein 10 was lower in BV-positive than in BV-negative women, suggesting its suppression as a potential immune evasion mechanism by BV-associated bacteria.<jats:named-content content-type="genus-species">Lactobacillus crispatus</jats:named-content>and<jats:named-content content-type="genus-species">Lactobacillus vaginalis</jats:named-content>were associated with decreased proinflammatory cytokines and each BV-associated species with increased proinflammatory cytokines. Remarkably, the<jats:italic>in vitro</jats:italic>anti-HIV activity of CVL samples from BV-positive women was stronger than that of BV-negative women. In conclusion, we found significant associations of factors, including vaginal microbiota, which can influence immune mediators i
Jespers V, Crucitti T, Menten J, et al., 2014, Prevalence and Correlates of Bacterial Vaginosis in Different Sub-Populations of Women in Sub-Saharan Africa: A Cross-Sectional Study, PLoS ONE, Vol: 9, Pages: e109670-e109670
Joseph S, Abbai N, Delaney-Moretlwe S, et al., 2014, Bacterial Vaginosis and HIV: An Analysis of the MDP301 Trial, AIDS Research and Human Retroviruses, Vol: 30, Pages: A232-A232, ISSN: 0889-2229
Chan AK, Ford D, Namata H, et al., 2014, The Lablite project: A cross-sectional mapping survey of decentralized HIV service provision in Malawi, Uganda and Zimbabwe, BMC HEALTH SERVICES RESEARCH, Vol: 14
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McKay PF, Cope AV, Mann JFS, et al., 2014, Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen, PLOS One, Vol: 9, ISSN: 1932-6203
Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNApoxvirus-proteinstrategy in mice and rabbits, administering MVA and protein immunizations either sequentially orsimultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/2GLA-AF adjuvant) andeither co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. TheDNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to theboost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccinecomponents. Moreover, a high proportion of the total mucosal IgG (20 – 50%) present in the vaginal vault of thesevaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccinemodality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIVCN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene productexpressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA andGLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequentialvaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit ofthe condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced,an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF.
Hendriksen ICE, White LJ, Veenemans J, et al., 2013, Defining Falciparum-Malaria-Attributable Severe Febrile Illness in Moderate-to-High Transmission Settings on the Basis of Plasma PfHRP2 Concentration, The Journal of Infectious Diseases, Vol: 207, Pages: 351-361, ISSN: 0022-1899
McKay PF, Cope AV, Swales J, et al., 2012, Antigen-specific T lymphocyte responses elicited by a DNA - MVA HIV CN54gp140 immunization regime are significantly altered by the TLR4 adjuvant GLA, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
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